Catharine J. Holberg

Asthma and wheezing in the first six years of life. The Group Health Medical Associates.

BACKGROUND Many young children wheeze during viral respiratory infections, but the pathogenesis of these episodes and their relation to the development of asthma later in life are not well understood. METHODS In a prospective study, we investigated the factors affecting wheezing before the age of three years and their relation to wheezing at six years of age. Of 1246 newborns in the Tucson, Arizona, area enrolled between May 1980 and October 1984, follow-up data at both three and six years of age was available for 826. For these children, assessments in infancy included measurement of cord-serum IgE levels (measured in 750 children), pulmonary-function testing before any lower respiratory illness had occurred (125), measurement of serum IgE levels at nine months of age (672), and questionnaires completed by the childrens parents when the children were one year old (800). Assessments at six years of age included measurement of serum IgE levels (in 460), pulmonary-function testing (526), and skin allergy testing (629). RESULTS At the age of six years, 425 children (51.5 percent) had never wheezed, 164 (19.9 percent) had had at least one lower respiratory illness with wheezing during the first three years of life but had no wheezing at six years of age, 124 (15.0 percent) had no wheezing before the age of three years but had wheezing at the age of six years, and 113 (13.7 percent) had wheezing both before three years of age and at six years of age. The children who had wheezing before three years of age but not at the age of six had diminished airway function (length-adjusted maximal expiratory flow at functional residual capacity [Vmax FRC]) both before the age of one year and at the age of six years, were more likely than the other children to have mothers who smoked but not mothers with asthma, and did not have elevated serum IgE levels or skin-test reactivity. Children who started wheezing in early life and continued to wheeze at the age of six were more likely than the children who never wheezed to have mothers with a history of asthma (P < 0.001), to have elevated serum IgE levels (P < 0.01), to have normal lung function in the first year of life, and to have elevated serum IgE levels (P < 0.001) and diminished values for VmaxFRC (P < 0.01) at six years of age. CONCLUSIONS The majority of infants with wheezing have transient conditions associated with diminished airway function at birth and do not have increased risks of asthma or allergies later in life. In a substantial minority of infants, however, wheezing episodes are probably related to a predisposition to asthma.

Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years.

BACKGROUND The relation between lower respiratory tract illnesses in early life caused by the respiratory syncytial virus (RSV) and the subsequent development of wheezing and atopy in childhood is not well understood. We studied this relation in children who had lower respiratory tract illnesses that occurred before 3 years of age. METHODS Children were enrolled at birth and cases of lower respiratory tract illness were ascertained by a physician. Viral tests were done for specimens collected at the time of the illness. Children were classified into five groups according to type and cause of lower respiratory tract illness. Children were then followed prospectively up to age 13, and we measured frequency of wheezing, pulmonary function, and atopic status (allergy skin-prick tests, serum IgE concentrations). FINDINGS RSV lower respiratory tract illnesses were associated with an increased risk of infrequent wheeze (odds ratio 3.2 [95% CI 2.0-5.0], p < 0.001), and an increased risk of frequent wheeze (4.3 [2.2-8.7], p < or = 0.001) by age 6. Risk decreased markedly with age and was not significant by age 13. There was no association between RSV lower respiratory tract illnesses and subsequent atopic status. RSV lower respiratory tract illnesses were associated with significantly lower measurements of forced expiratory volume (2.11 [2.05-2.15], p < or = 0.001) when compared with those of children with no lower respiratory tract illnesses, but there was no difference in forced expiratory volume after inhalation of salbutamol. INTERPRETATION RSV lower respiratory tract illnesses in early childhood are an independent risk factor for the subsequent development of wheezing up to age 11 years but not at age 13. This association is not caused by an increased risk of allergic sensitisation.

SIBLINGS, DAY-CARE ATTENDANCE, AND THE RISK OF ASTHMA AND WHEEZING DURING CHILDHOOD

BACKGROUND Young children with older siblings and those who attend day care are at increased risk for infections, which in turn may protect against the development of allergic diseases, including asthma. However, the results of studies examining the relation between exposure to other children and the subsequent development of asthma have been conflicting. METHODS In a study involving 1035 children followed since birth as part of the Tucson Childrens Respiratory Study, we determined the incidence of asthma (defined as at least one episode of asthma diagnosed by a physician when the child was 6 to 13 years old) and the prevalence of frequent wheezing (more than three wheezing episodes during the preceding year) in relation to the number of siblings at home and in relation to attendance at day care during infancy. RESULTS The presence of one or more older siblings at home protected against the development of asthma (adjusted relative risk for each additional older sibling, 0.8; 95 percent confidence interval, 0.7 to 1.0; P=0.04), as did attendance at day care during the first six months of life (adjusted relative risk, 0.4; 95 percent confidence interval, 0.2 to 1.0; P=0.04). Children with more exposure to other children at home or at day care were more likely to have frequent wheezing at the age of 2 years than children with little or no exposure (adjusted relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.8; P=0.01) but were less likely to have frequent wheezing from the age of 6 (adjusted relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0; P=0.03) through the age of 13 (adjusted relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). CONCLUSIONS Exposure of young children to older children at home or to other children at day care protects against the development of asthma and frequent wheezing later in childhood.

Diminished Lung Function as a Predisposing Factor for Wheezing Respiratory Illness in Infants

In a prospective study of 124 infants enrolled as newborns, we assessed the relation between initial lung function and the subsequent incidence of lower respiratory tract illness during the first year of life. The risk of having a wheezing illness was 3.7 times higher (95 percent confidence interval, 0.9 to 15.5; P = 0.06) among infants whose values for total respiratory conductance (the reciprocal of the resistance to air flow of the entire respiratory system) were in the lowest third, as compared with infants with values in the upper two thirds of the range of values for the group. Boys with initial values in the lowest third for an indirect index of airway conductance had a 10-fold increase (95 percent confidence interval, 2.2 to 44.2; P = 0.001) in the risk of having a wheezing illness. A 16-fold increase (95 percent confidence interval, 1.7 to 147.1; P = 0.002) in the risk of having a wheezing illness was found among girls whose initial values for lung volume at the end of tidal expiration were in the lowest third. We conclude that diminished lung function is a predisposing factor for the development of a first wheezing illness in infants.

Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood

BACKGROUND The relationship between infant feeding and childhood asthma is controversial. This study tested the hypothesis that the relation between breast feeding and childhood asthma is altered by the presence of maternal asthma. METHODS Healthy non-selected newborn infants (n=1246) were enrolled at birth. Asthma was defined as a physician diagnosis of asthma plus asthma symptoms reported on ⩾2 questionnaires at 6, 9, 11 or 13 years. Recurrent wheeze (⩾4 episodes in the past year) was reported by questionnaire at seven ages in the first 13 years of life. Duration of exclusive breast feeding was based on prospective physician reports or parental questionnaires completed at 18 months. Atopy was assessed by skin test responses at the age of 6 years. RESULTS The relationship between breast feeding, asthma, and wheeze differed with the presence or absence of maternal asthma and atopy in the child. After adjusting for confounders, children with asthmatic mothers were significantly more likely to have asthma if they had been exclusively breast fed (OR 8.7, 95% CI 3.4 to 22.2). This relationship was only evident for atopic children and persisted after adjusting for confounders. In contrast, the relation between recurrent wheeze and breast feeding was age dependent. In the first 2 years of life exclusive breast feeding was associated with significantly lower rates of recurrent wheeze (OR 0.45, 95% CI 0.2 to 0.9), regardless of the presence or absence of maternal asthma or atopy in the child. Beginning at the age of 6 years, exclusive breast feeding was unrelated to prevalence of recurrent wheeze, except for children with asthmatic mothers in whom it was associated with a higher odds ratio for wheeze (OR 5.7, 95% CI 2.3 to 14.1), especially if the child was atopic. CONCLUSION The relationship between breast feeding and asthma or recurrent wheeze varies with the age of the child and the presence or absence of maternal asthma and atopy in the child. While associated with protection against recurrent wheeze early in life, breast feeding is associated with an increased risk of asthma and recurrent wheeze beginning at the age of 6 years, but only for atopic children with asthmatic mothers.

Breast feeding and lower respiratory tract illness in the first year of life. Group Health Medical Associates.

OBJECTIVE--To assess the relation between breast feeding and subsequent experience of lower respiratory tract illness. DESIGN--Prospective (from well child visits) and retrospective (from maternal recall) study of breast feeding and prospective assessment by paediatricians of lower respiratory tract illness in infants during first year of life. SETTING--Health maintenance organisation. PARTICIPANTS--Over 1000 infants who were healthy at birth and whose parents used the paediatricians of a local health maintenance organisation. MAIN OUTCOME MEASURES--Duration of breast feeding and type of lower respiratory tract illness (wheezing and non-wheezing) at different age intervals during the first year of life. RESULTS--Breast feeding was associated with a decreased incidence of wheezing illnesses only in the first four months of life. Interactions existed between breast feeding and sharing a room, being Mexican American, and being a boy. Multivariate techniques showed that after controlling for a variety of factors children who received minimal breast milk had a greater risk of early wheezing illnesses; the risk was further increased by simultaneous exposure to sharing a room. CONCLUSION--Breast feeding seems to protect against wheezing respiratory tract illnesses in the first four months of life, particularly when other risk factors are present.

Association of interleukin-2 and interferon-γ production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy

The mechanisms regulating the onset of atopic sensitization in human beings are not yet fully clarified. We assessed the capacity of mitogen-stimulated umbilical and peripheral blood mononuclear cells to produce interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) at birth and at 9 months of age in 159 infants. Mononuclear cell production of both IFN-gamma and IL-2 at 9 months, but not at birth, was found to be inversely related to parental immediate skin test reactivity to seven local aeroallergens. Skin test reactivity at the age of 6 years was also inversely related to IFN-gamma and IL-2 production at 9 months of age. However, no relationship was evident between total serum IgE levels at 6 years and production of these cytokines at 9 months. The proportions of circulating lymphocytes and CD4+ or CD8+ cells were also unrelated to skin test reactivity at the age of 6 years. These data suggest that mechanisms regulating skin test reactivity to inhaled allergens may involve deficient IFN-gamma production, deficient IL-2 production, or both during or preceding the time of initial sensitization and that additional mechanisms are involved in regulating total serum IgE level.

Relationship of parental smoking to wheezing and nonwheezing lower respiratory tract illnesses in infancy

The relationship between parental smoking and lower respiratory tract illness (LRI) was studied in a large cohort of infants followed prospectively from birth. Illnesses were diagnosed by physicians using agreed-on criteria, and parental smoking histories were obtained by questionnaire. The LRIs were differentiated into wheezing and nonwheezing episodes, and the age at first illness of either type was evaluated in relation to smoking by parents. The odds of having an LRI were significantly higher in children whose mothers smoked (odds ratio 1.52; confidence interval 1.07 to 2.15). The odds were higher if the mother smoked a pack of cigarettes or more per day and if the child stayed home rather than attending day care (odds ratio 2.8; confidence interval 1.43 to 5.5). Logistic regression indicated that the LRI rate was significantly elevated both in children exposed to heavy maternal smoke in the absence of day care, and in those who use day care but were not exposed to maternal smoking of a pack or more per day. These findings could not be attributed to other confounding variables. Neither paternal smoking nor smoking by other household members was consistently related to the LRI rate. The relationship of maternal smoking to LRI rate was evident for both wheezing and nonwheezing illnesses. Maternal smoking of a pack or more per day was also related to an early age at first LRI, for both wheezing (p less than 0.05) and nonwheezing (p less than 0.002) illnesses. In sum, maternal smoking is associated with a higher rate of LRIs in the first year, particularly when mothers smoked a pack or more per day and when the child did not use day care.

Total serum IgE and its association with asthma symptoms and allergic sensitization among children

BACKGROUND Asthma and wheezing during childhood are associated with elevated total serum IgE and with allergic sensitization to local aeroallergens. However, little is known about the longitudinal relationship between total serum IgE and the development of wheezing and allergic sensitization during childhood. OBJECTIVE The purpose of our investigation was to determine the relationship between total serum IgE and the development of wheezing and allergic sensitization in childhood. METHODS Our study subjects were participants in the Tucson Childrens Respiratory Study who underwent an IgE measurement in at least 1 of 3 surveys (at years 1, 6, and 11) and complete allergy skin tests during the latter 2 surveys. The childrens phenotypes were categorized on the basis of skin test response (never, early, and late) and wheezing status (never, early, late, and persistent). Repeated-measures analyses were used, allowing subjects to be included who had unequal numbers of IgE observations (a total of 263 boys and 277 girls). RESULTS We found that total serum IgE levels track with age: subjects with high serum IgE levels less than 1 year old continued to have high IgE levels at ages 6 and 11 years. Both persistent wheezing and early sensitization were associated with high serum IgE levels at all ages. Boys who had late or persistent wheezing or who were sensitized early or late had high serum IgE levels as early as age 9 months, whereas only girls with persistent wheezing and early sensitization had elevated IgE levels at that age. Children who wheezed only in the first years of life and not after (ie, those with early wheezing) had serum IgE levels that were not different from those of nonwheezing children. CONCLUSION On the basis of these findings we conclude that although total serum IgE tracks with age, children who are predisposed to persistent wheezing and early sensitization to local aeroallergens already have high levels of IgE at age 9 months. This suggests that the predisposition to respond to environmental stimuli through high levels of IgE precede early allergic sensitization, indicating that there may be a common defect in the development of the immune system involving IgE production and early allergic sensitization.

Breast-feeding, maternal IgE, and total serum IgE in childhood☆☆☆★

BACKGROUND There is controversy regarding the relationship of the effect of breast-feeding on markers of allergy such as total serum IgE in childhood. OBJECTIVE This study, using longitudinal data, tested the hypothesis that the relation of breast-feeding to IgE in childhood differs depending on maternal total IgE level. METHODS Total serum IgE was assessed with the paper radioimmunosorbent test at 4 ages in nonselected children enrolled at birth into the prospective Tucson Childrens Respiratory Study. Children were classified as never breast-fed, breast-fed less than 4 months, or breast-fed 4 months or longer, on the basis of physician report or questionnaires completed by parents by the time the child was 18 months old. A longitudinal random effects model was used to test for group differences and temporal trends in IgE for children classified with reference to maternal IgE (high tertile vs all others) and breast-feeding history. A total of 664 children with 1457 observations were included. RESULTS Among children whose mothers were in the 2 lower tertiles of IgE, breast-feeding was associated with lower total serum IgE at age 6 years (24.2 vs 44.3 IU/mL for never breast-fed children; P <.02); similar trends existed at age 11 years. In contrast, for children whose mothers were in the highest tertile of IgE, breast-feeding of 4 months or longer was associated with higher IgE levels in the child compared with those never breast-fed or breast-fed less than 4 months (97.0 vs 38.9 IU/mL; P <. 005). These cross-sectional analyses were confirmed with the longitudinal random effects model, which also showed no effect of confounders. Paternal IgE showed no similar relation with child IgE. CONCLUSION Breast-feeding appears to have paradoxic relations with IgE in childhood, depending on maternal IgE level. These findings may help explain the contradictory results found in other investigations of the relation of breast-feeding to allergic symptoms and markers.